Project 2 of our program project proposal is entitled "Gene therapy for bladder pain" (P.I.: Naoki Yoshimura,[unreadable] Department of Urology). This is a preclinical study that will investigate a gene therapy approach in the[unreadable] treatment of visceral pain in the lower urinary tract (LUT).[unreadable] Interstitial cystitis (1C) is a painful bladder syndrome of unknown etiology, characterized by chronic pelvic[unreadable] pain, urinary frequency and urgency. It affects an estimated 450,000 people in the United States. Despite[unreadable] this high incidence the pain-related symptoms in patients with 1C are often very difficult to treat; therefore[unreadable] new therapies are desperately needed for the many sufferers with refractory 1C. In this research project, we[unreadable] propose a novel gene therapy strategy using herpes simplex virus (HSV)-based vectors to treat pain in[unreadable] several rodent models of visceral pain of the LUT. By utilizing the natural biology of HSV, HSV-based[unreadable] vectors can deliver gene products directly to target organ-specific sensory pathways such as those[unreadable] innervating the bladder, urethra, and pelvic floor. We will use two approaches for our treatment strategy.[unreadable] The first will employ HSV vectors containing the proenkaphlin or glutamic acid decarboxylase (GAD) gene in[unreadable] order to increasing the amount of the endogenous opioid peptide enkepahlin or the inhibitory[unreadable] neurotransmitter gamma-amino butyric acid (GABA) within the dorsal horn (DH) of the spinal cord. The second[unreadable] approach will employ HSV vectos containing the anti-inflammatory interleukin-4 (IL-4) or truncated tumor[unreadable] necrosis factor alpha receptor (TNFalphaSR) genes in order to reduce the inflammatory response either in the[unreadable] DH or the target organ.[unreadable] The outcomes of the experiments proposed here we will determine several important issues: (1) HSV-based[unreadable] viral vectors can transfer therapeutic genes to afferent pathways after local injections into the different[unreadable] portions of the LUT, (2) HSV vector-mediated transgene expression in bladder afferent pathways can[unreadable] prevent and/or reverse pain and irritation of the LUT in the different animal models of acute C-fiber[unreadable] sensitization, (3) HSV vector-mediated transgene expression can also have therapeutic effects on[unreadable] nociceptive responses and/or urinary frequency induced by C-fiber hyperexcitability in chronic animal models[unreadable] of tissue inflammation or nerve injury in the LUT.[unreadable] The long-term objectives of the research program are to establish a safe and effective method of gene[unreadable] therapy using HSV vectors carrying therapeutic genes for the treatment of chronic bladder and/or pelvic pain[unreadable] associated with painful bladder syndromes including 1C.